Early vs Delayed Levodopa Therapy in Patients With Early Parkinson's Disease

Oftentimes, a multitude of well-designed studies fail to portray the arc of a long, progressive chronic disease, where people increasingly live for 20 years and more after diagnosis. The study by Frequin et al did not find a difference in the rate of disease progression or in the prevalence of motor complications between patients with early Parkinson's disease (PD) starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. However, 5 years of disease progression still marks the early years of PD, a period when the extrapyramidal pathways with their surviving dopaminergic neurons continue to have sufficient compensatory reserve to buffer vacillations in dopamine concentrations. What will happen over the next 5, 10, and 15 years as the number of surviving neurons continue to decline?

The key underlying question is whether motor complications are caused by levodopa treatment duration, cumulative levodopa dose, or disease duration, and the authors cite a relatively small well-designed case–control study that compared patients who started levodopa therapy relatively late because of lack of access with patients who started levodopa therapy earlier. The results showed that motor complications were not associated with levodopa treatment duration, but instead with disease duration and a higher levodopa daily dose.¹ Indeed, clinical experience with patients who receive levodopa very late or, conversely, patients with a short disease duration and excessive levodopa use are instructive. Fortunately, relatively few patients go undiagnosed or untreated for more than 10 years; however, in these rare situations, a robust response to levodopa is commonly followed by the rapid emergence of motor fluctuations and/or dyskinesias within a period of months. Conversely, patients with dopamine dysregulation syndrome who self-administer 2 to 4 grams of levodopa for early to mid-stage PD develop disproportionately severe fluctuations and dyskinesia.

Although not reaching statistical significance, this study shows a trend toward greater worsening of the total UPDRS score in the early-start group compared with the delayed-start group, which increases from the 3-year to 5-year timepoints (mean difference in the total UPDRS score at 3 years: 1.7 points and at 5 years: 3.3 points). Although this difference is below the minimum clinically important difference for the total UPDRS score (4.3 points), the mean difference in the UPDRS III (motor) score exceeds the minimum clinically important difference of 2.5 points (mean difference in the motor UPDRS score at 3 years: 1.4 points and at 5 years: 2.7 points). Indeed, the motor UPDRS score may have been the better primary outcome for this study because it includes a greater proportion of levodopa responsive signs than the total UPDRS score. The trend of a widening difference between the early-start and delayed-start groups between 3 and 5 years, with P values beginning to approach significance, suggests that the differences are likely to reach significance over longer periods of time (5–10 years of follow-up) during the period when motor and nonmotor complications commonly develop.

This well-designed study enhances clinicians' understanding of the effects of earlier versus later introduction of levodopa in patients with PD, but a more accurate title for the study would be "Longer-Term Follow-Up of the LEAP Study," and questions about long-term disease modification continue.

References

1. Cilia R, Akpalu A, Sarfo FS, et al. The Modern Pre-Levodopa Era of Parkinson’s Disease: Insights Into Motor Complications From Sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-2742. https://academic.oup.com/brain/article/137/10/2731/2847277

2. Shulman LM, Gruber-Baldini AL, Anderson KE, et al. The Clinically Important Difference on the Unified Parkinson’s Disease Rating Scale. Arch Neurol. 2010;67(1):64-70. https://jamanetwork.com/journals/jamaneurology/fullarticle/799064